KR960008651B1 - Therapeutic preparation for the treatment of hepatic disorders - Google Patents
Therapeutic preparation for the treatment of hepatic disorders Download PDFInfo
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- KR960008651B1 KR960008651B1 KR1019880004617A KR880004617A KR960008651B1 KR 960008651 B1 KR960008651 B1 KR 960008651B1 KR 1019880004617 A KR1019880004617 A KR 1019880004617A KR 880004617 A KR880004617 A KR 880004617A KR 960008651 B1 KR960008651 B1 KR 960008651B1
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
Abstract
내용없음.None.
Description
제1도 및 제2도는 실시예 1에서의 혈장 에탄올 농도와 각성 상태에 관한 시험 결과를 나타낸 도면이며,1 and 2 are diagrams showing test results regarding plasma ethanol concentration and arousal state in Example 1,
제3도는 실시예 2에서의 생존율에 관한 실험 결과를 나타낸 도면이고,3 is a view showing the results of the experiment on the survival rate in Example 2,
제4도는 실시예 3에서의 각종 활성에 관한 실험 결과를 나타낸 도면이며,4 is a view showing the results of the experiment on the various activities in Example 3,
제5도는 실시예 5에서의 간기능 검사치의 경과를 나타낸 도면이다.5 is a diagram showing the progress of liver function test values in Example 5. FIG.
본 발명은 특히 알콜성 간장해 치료효과와 예방효과가 있는 신규한 약제 및 식품에 관한 것이다.The present invention relates in particular to novel drugs and foods having a therapeutic and prophylactic effect on alcoholic liver injury.
알콜은 주로 간장에서 대사되기 때문에, 장기간에 걸쳐 다량의 알콜을 섭취한 경우에는 지방간, 알콜성 간염 또는 간경변 등과 같이 주로 간장에 장해가 유발된다.Since alcohol is mainly metabolized in the liver, when a large amount of alcohol is ingested over a long period of time, the liver is mainly disturbed, such as fatty liver, alcoholic hepatitis, or cirrhosis.
이러한 알콜성 간 장해를 경감시키거나, 또는 치유하는 목적에서는 금주를 기본으로 하여 비타민 제제, 인지질 제제, 부신피질 호르몬제, 인슐린 제제 등의 약제를 보조용법적으로 사용하고 있는 이외에, 글루쿠론산 제제 및 아미노산 제제(예 : 아르기닌 염산염등)를 사용하고 있지만, 치료 도중에도 음주 습관을 지속하는 경우도 많아 반드시 충분한 효과가 수득되지 않고 있는 것이 현재의 상태이다.For the purpose of alleviating or healing such alcoholic liver disorders, glucuronic acid preparations are used in addition to the use of drugs such as vitamin preparations, phospholipid preparations, corticosteroids, insulin preparations, etc. on the basis of this week. And amino acid preparations (eg, arginine hydrochloride, etc.), but the drinking habit is often maintained even during the treatment, and a sufficient effect is not obtained at present.
최근에, 급성 알콜 중독 마우스에 아미노산을 투여함으로써 구명 효과가 있는 것으로 밝혀졌으며, 특히 알라닌과 오르니틴을 동시에 투여하면 효과가 현저하다(참조 : 일본국 공개 특허공보 제(소)61-50917호). 또한, 본 발명자들은, 장기간 동안 대량의 에탄올을 섭취한 래트에서는 알라닌과 글루타민에 대한 기호성이 높아지며, 급성 에탄올 중독 래트에서는 양자를 동시에 투여함으로써 혈중 에탄올의 소실, 혼수 상태로부터의 회복 및 행동 억제의 정상화에서 강한 촉진 효과가 있음을 확인하였지만, 장해도가 큰 알콜성 간 장해에 대한 치료 효과나 예방 효과는 도저히 추정할 수 없다. 음주에 의한 혈중 아세트알데히드 농도의 상승이 급성의 악취 증상과 관계 있음을 주목하여 래트에게 알라닌, 글루탐산, 아스파라긴산을 미리 투여한 경우 이러한 아미노산에 의한 아세트알데히드의 독성 저감 효과를 나타낸 보고도 있지만, 이러한 경우에도 혈청중 간유래 효소 활성의 개선 효과는 확인되지 않았다(참조 : 일본국 공개 특허공보 제(소)61-134313호).Recently, it has been found to have a life-saving effect by administering amino acids to acute alcoholic mice, especially when alanine and ornithine are administered simultaneously (see Japanese Patent Laid-Open No. 61-50917). . In addition, the present inventors have found that palatability to alanine and glutamine is increased in rats ingested a large amount of ethanol for a long period of time, and normalization of blood ethanol loss, recovery from coma and behavior inhibition by simultaneous administration of both in acute ethanol poisoning rats. Although it has been confirmed that there is a strong promoting effect, the therapeutic effect or preventive effect on alcoholic liver disorders with large intestinal tract cannot be estimated. It is noted that the increase in acetaldehyde level in the blood by drinking alcohol is associated with acute malodor symptoms, and rats were previously treated with alanine, glutamic acid, and aspartic acid to reduce the toxicity of acetaldehyde by these amino acids. The effect of improving liver-derived enzyme activity in serum was not confirmed (see Japanese Patent Application Laid-open No. 61-134313).
상습 음주자의 경우, 알콜성 간 장해의 치료에서는 주로 간 장해, 특히 간 실질세포의 장해 개선과 진행억제에 주안점을 두고 있지만, 만성화된 경우에는 완치하기가 곤란하다. 특히, 알콜성 간 장해에 수반하여 발생하는 간유래 혈청중 효소 활성치의 정상화는 음주 습관의 지속으로 매우 곤란하다. 따라서, 이러한 간장해의 치료와 예방을 가능케하는 약제의 개발이 요망된다.In the case of habitual drinkers, alcoholic liver disorders are mainly focused on improving liver disorders, particularly liver parenchymal cell disorders and inhibiting progression, but are difficult to cure in chronic cases. In particular, normalization of enzyme activity in liver-derived serum that occurs with alcoholic liver disorder is very difficult due to the persistence of drinking habits. Therefore, the development of a medicament that enables the treatment and prevention of such liver disorders is desired.
우선 본 발명자들은 래트에게 에탄올을 경구 투여한 경우, 각종 혈장 아미노산 중에서 알라닌과 글루타민 농도가 현저하게 감소하는 것을 인지하였으며, 알라닌과 글루타민을 동시에 투여함으로써 에탄올 섭취에 수반하는 각종 증상(저혈당, 에탄올 잔류, 혼수 상태 및 행동 억제)이 회복되는 것을 밝혀내었지만, 알콜성 간 장해의 지표인 혈청중 간유래 활성효소의 개선 효과면에서의 검토는 충분하게 수행되지 않았다.First of all, the present inventors noticed a significant decrease in alanine and glutamine concentrations among various plasma amino acids when ethanol was orally administered to rats, and various symptoms associated with ethanol intake by simultaneous administration of alanine and glutamine (hypoglycemia, ethanol residue, Coma and behavioral suppression) have been found to be recovered, but studies on the improvement effect of liver-derived activating enzymes in serum, which are indicative of alcoholic liver failure, have not been conducted sufficiently.
따라서, 본 발명자들은 알라닌과 글루타민의 동시 투여에 의한 알콜성 간 장해 치료약으로서의 가능성을 확인하기 위해 급성 알콜성 간염 모델 래트를 작제하고 혈청중 간 유래 효소활성의 개선효과와 알콜성 간장해 환자에 대한 치료 효과를 지표로 알라닌과 글루타민의 배합비 및 사람에 대한 투여량을 검토하였다.Therefore, the present inventors constructed acute alcoholic hepatitis model rats to confirm the potential as a drug for the treatment of alcoholic liver disorder by simultaneous administration of alanine and glutamine, and the effect of improving the enzyme activity in liver and serum of the liver. As the index of treatment effect, the combination ratio of alanine and glutamine and the dose to humans were examined.
본 발명자들은 통상, 래트에게 알콜을 투여한 경우에는 치사량에 가까운 양을 투여해도 래트의 혈중 알콜량은 비교적 신속하게 소실되며 급성 알콜성 간염 증상을 나타내지 않는 것을 알았다. 또한, 래트의 장기간 에탄올 섭취에 의한 만성 간 장해 모델의 작제에 대해서도 여러가지로 연구되고 있지만, 현재에는 반드시 충분하지 않다.The present inventors have found that, in the case of administering an alcohol to rats, even if an amount close to the lethal dose is lost, the blood alcohol content of the rat is relatively rapidly lost and does not exhibit symptoms of acute alcoholic hepatitis. In addition, various studies have been made on the construction of a model of chronic liver injury caused by rats' long-term ethanol intake, but it is not always sufficient.
따라서, 본 발명자들은 에탄올과 함께 미량의 하이드라진 설페이트를 동시투여함으로써 래트 혈중 에탄올의 소실은 지연되고, 급성 알콜 중독 증상은 악화되며, 본 모델은 혈청중 간유래 효소 활성[글루탐산 옥살로 아세트산 아미노기 전이효소(GOT), 글루탐산 피루브산 아미노기 전이효소(GPT) 및 오르니틴 카바밀기 전이효소(OCT)]이 상승하여 급성 알콜성 간염증상을 나타내는 것을 밝혀내었다. 또한, 이러한 간장해는 단백질 섭취량에 비례하여 악화되는 경향을 나타내고 있다.Therefore, the present inventors co-administered a trace amount of hydrazine sulfate with ethanol to delay the loss of ethanol in the blood of the rat, aggravate acute alcoholism symptoms, and present model shows that hepatic-derived enzyme activity [glutamic acid oxalo acetate amino group transferase (GOT), glutamic acid pyruvate amino group transferase (GPT) and ornithine carbamyl transferase (OCT)] have been shown to show acute alcoholic hepatitis symptoms. In addition, such liver disorders tend to worsen in proportion to protein intake.
따라서, 본 발명자들은 알라닌 단독, 글루타민 단독 및 알라닌과 글루타민을 각종 비율로 혼합한 조성물을 미리 투여하고 에탄올과 하이드라진 설페이트를 경구투여하며 혈중에탄올의 소실 촉진 효과와 혈청 중 간유래 효소 활성의 상승억제 효과를 지표로 알라닌과 글루타민의 최적 병용 비율을 구하여 본 발명을 완성하기에 이르렀다.Therefore, the present inventors previously administered alanine alone, glutamine alone, and a mixture of alanine and glutamine in various ratios, and oral administration of ethanol and hydrazine sulfate, the effect of promoting the loss of ethanol in the blood and synergistic inhibitory effect of liver-derived enzyme activity in serum The present invention was completed by finding an optimal combination ratio of alanine and glutamine as an index.
즉, 본 발명은 알라닌과 글루타민을 1 : 0.1 내지 10의 몰비로 함유하는 간 장해 치료 및 예방제이다. 예를 들면, 알콜성 간 장해에 유효하다. 알라닌이나 글루타민은 L체, D체 및 DL체를 불문하지만 천연에 존재한다는 점에서 L체가 바람직하다.That is, the present invention is an agent for treating and preventing liver disorders containing alanine and glutamine in a molar ratio of 1: 0.1 to 10. For example, it is available for alcoholic liver disorders. Although alanine and glutamine are L-, D-, and DL-forms, L-form is preferable in that it exists in nature.
또한, 알라닌이나 글루타민은 유리 형태라도, 염 형태라도 상관없으며, 양자에 의한 펩타이드형이라도 상관없다.In addition, alanine and glutamine may be free form or salt form, and may be a peptide form by both.
성인, 예를 들면, 체중이 40 내지 70kg인 성인 1일당 알라닌과 글루타민의 합계이자 유리체로 환산하여 1 내지 20g을 경구 섭취할 수 있도록 한 것이다.Adults, for example, weight of 40 to 70kg of alanine and glutamine per day in the total and in terms of vitreous to 1 to 20g oral intake.
본 발명에서는 알라닌과 글루타민이 일정한 몰비로 존재하는 것이 바람직하며, 따라서 혼합 함유는 물론 물리적으로 개별적으로 존재하고 있어도 사용시에 조합할 수 있도록 한 것이어도 상관 없다.In the present invention, it is preferable that alanine and glutamine are present in a constant molar ratio. Therefore, even if they are present in a mixed content as well as physically individually, they may be combined at the time of use.
혈중 알콜의 소실 촉진 효과와 알콜 섭취에 수반하는 행동억제(사망까지를 포함)의 경감 효과면에서는 글루타민 단독 또는 알라닌보다 글루타민의 비율이 큰 조성물이 바람직한 것을, GOT, GPT, OCT 활성의 상승 억제 효과면에서는 알라닌 단독 또는 글루타민보다 알라닌의 비율이 큰 조성물이 바람직한 것을 알아내었다. 이러한 발견으로부터 수득한 알라닌과 글루타민의 병용 비율은 몰 농도비로 1 : 0.1 내지 10이며, 특히 1 : 에서 이의 효과가 현저하다. 또한, 이러한 발견을 근거로 알콜성 간 장해 환자에게 알라닌과 글루타민의 조성물(몰 농도비 1 : 0.13)을 1일당 3g 계속 경구 투여하여 알콜성 간 장해 환자의 진단에 유용한 효소 γ-글루타밀트란스펩티다제(γ-GTP) 이외에 GOT, GPT 등의 간유래 효소의 활성 저하를 지표로 본 발명의 조성물의 임상적 효과를 검토한 결과, 동물 실험에서 급성 알콜성 간염의 검토 결과를 뒷받침하는 성적이 수득된다. 특히, γ-GTP의 저하 작용을 나타내는 약제가 적은 현상태에서는 본 발명에 의거한 내용은 주목할 가치가 있다고 생각된다. 알라닌과 글루타민의 조성물의 사람에 대한 경구투여량은 투여기간의 길이에도 좌우되지만, 약제로서의 예방효과와 치료 효과를 기대하는데에는 성인 1일당 1g 이상이 바람직하며, 상한에 대해서는 복용하기 쉬운 양으로서 20g 이하가 바람직하다.In view of the effects of promoting the loss of alcohol in the blood and reducing the effects of inhibiting the behavior (including death) associated with alcohol consumption, glutamine alone or a composition with a greater ratio of glutamine than alanine is preferred. In terms of alanine, compositions having alanine greater than alanine alone or glutamine were found to be preferable. The combined ratio of alanine and glutamine obtained from these findings is from 1: 0.1 to 10 in molar concentration ratio, particularly at 1: 1. Based on these findings, the enzyme γ-glutamyltranspeptide is useful for the diagnosis of alcoholic liver disorders by continuously oral administration of a composition of alanine and glutamine (molar ratio 1: 0.13) to the alcoholic liver disorder patients 3 moles per day. In addition to (γ-GTP), the clinical effect of the composition of the present invention was examined as an indicator of the deactivation of liver-derived enzymes such as GOT and GPT, and the results supporting the findings of acute alcoholic hepatitis in animal experiments were obtained. do. In particular, it is considered that the contents based on the present invention are worth noting in a state where there are few drugs exhibiting a lowering effect of γ-GTP. The oral dose of alanine and glutamine in humans depends on the length of the administration period, but in order to expect prophylactic and therapeutic effects as a medicament, 1 g or more per adult is preferred, and 20 g as an easy to take amount for the upper limit. The following is preferable.
알라닌과 글루타민은 생체내에서 알라닌 또는 글루타민으로서 유효하게 작용하면 염 또는 기타의 유도체라도 사용할 수 있다.Alanine and glutamine may be used as salts or other derivatives as long as they effectively act as alanine or glutamine in vivo.
본 발명의 조성물은 병용비율과 섭취량을 보증할 수 있으면 의약품 또는 식품 형태로 제공할 수 있다. 예를 들면 의약품으로서는 산제, 과립, 정제, 당의정, 캅셀, 액제 등이며, 식품으로서는 알콜류와 동시에, 또는 상 전후에 섭취할 수 있는 식품에 본 조성물을 함유한 것이나 드링크류 또는 츄잉검류, 사탕류가 바람직하다.The composition of the present invention can be provided in the form of medicines or foods if the combination ratio and intake can be guaranteed. For example, medicines include powders, granules, tablets, dragees, capsules, liquids, and the like. Foods containing the present composition in foods that can be ingested at the same time as alcohols or before and after the food, and drinks, chewing gums, and candy are preferred. Do.
또한, 본 발명의 조성물은 알라닌과 글루타민을 필수유효 성분으로서 상기한 일정 몰비로 함유하지만, 기타의 아미노산류의 공존은 본 발명의 목적을 이탈하지 않는 한 가능한 것은 말할 필요도 없다.In addition, although the composition of this invention contains alanine and glutamine as an essential active ingredient in the above-mentioned fixed molar ratio, it cannot be overemphasized that coexistence of other amino acids is possible unless it deviates from the objective of this invention.
이하, 실시예에 따라 본 발명을 다시 설명한다.Hereinafter, the present invention will be described again according to the examples.
[실시예 1]Example 1
체중이 300 내지 340g인 생후 10주의 스프라그-돌리 수컷 래트에게 50% 정제 전란단백함유 사료를 1일동안 제공한다. 익일의 밝은 기간(오전 7시부터 오후 7시까지)에 4시간 동안 급식을 중단(오전 9시부터 오후 1시까지)한 다음, L-알라닌 또는 L-글루타민 단독 또는 양자의 배합 조성물을 0.3% 카복시메틸셀룰로오즈(CMC) 수용액에 현탁시켜 등질소량 투여(201mg 질소/kg 체중, 경구투여)하고, 1시간 후에 20% 에탄올 함유 생리식염수에 0.13% 하이드라진 설페이트를 첨가하여 투여(6.0g 에탄올 및 39mg 하이드라진설페이트/kg 체중, 경구투여)한다. 에탄올을 부하한지 3시간 및 24시간 후에 쇄골하정맥으로부터 채혈하고, 대조용(CMC 수용액 투여)을 포함하여 혈중 에탄올 농도를 조사하는 동시에 혼수 상태 등의 행동 관찰을 수행하고, 그룹간을 비교한다. 혈중 에탄올 농도는 투여후 3시간에서 글루타민 단독으로 저하되지만 알라닌과 글루타민의 배합조성물에서는 양자의 몰비가 1 : 1 이상에서 현저한 효과가 확인되었다. 이러한 경향은 에탄올 투여후 24시간에서 보다 명료하였다(제1도참조).10 week old Sprague-Dawley male rats weighing 300-340 g are given a 50% purified whole egg protein-containing feed for 1 day. Stop feeding for 4 hours (from 9:00 am to 1:00 pm) in the bright period of the next day (7 am to 7 pm), then add 0.3% of L-alanine or L-glutamine alone or a combination of both Suspension in isopropyl solution (201 mg nitrogen / kg body weight, oral administration) in suspension of aqueous solution of carboxymethyl cellulose (CMC), followed by administration of 0.13% hydrazine sulfate to 20% ethanol-containing saline solution (6.0 g ethanol and 39 mg hydrazine) Sulfate / kg body weight orally). 3 hours and 24 hours after ethanol loading, blood was collected from the subclavian vein, and blood (including aqueous solution of CMC) was examined, blood ethanol concentration was examined, and behavioral observation such as coma was performed, and the groups were compared. Serum ethanol concentration decreased to glutamine alone at 3 hours after administration, but in the combination composition of alanine and glutamine, a significant effect was found at the molar ratio of 1: 1 or more. This trend was clearer at 24 hours after ethanol administration (see Figure 1).
한편, 에탄올을 부하한 후의 혼수 및 각성에 대해서는, 3시간에서는 본 발명의 조성물의 투여효과가 확인되지 않았으며, 20시간에서는 알라닌 단독으로도 증상이 개선되었지만, 조성물중의 글루타민의 비율이 상승함에 따라 효과는 명백하게 되어, 양자의 몰비가 1 : 1 이상에서 편평하게 된다(제2도 참조).On the other hand, for coma and arousal after ethanol loading, the administration effect of the composition of the present invention was not confirmed at 3 hours, and symptoms were improved with alanine alone at 20 hours, but the ratio of glutamine in the composition was increased. As a result, the effect becomes apparent, and the molar ratio of both becomes flat at 1: 1 or more (see FIG. 2).
[실시예 2]Example 2
체중이 300 내지 340g인 생후 10주의 스프라그-돌리 수컷 래트에게 50% 정제 전란 단백 함유 사료를 1일 동안 제공한다. 익일의 밝은 기간(오전 7시부터 오후 7시까지)에 4시간 동안 급식을 중단(오전 9시부터 오후 1시까지)한 다음, L-알라닌 또는 L-글루타민 단독 또는 양자의 배합 조성물을 0.3% 카복시메틸셀룰로오즈(CMC) 수용액에 현탁시켜 등질소량 투여(201ml 질소/kg 체중, 경구투여)하고, 1시간 후에 20% 에탄올 함유 생리식염수에 0.11% 하이드라진 설페이트를 첨가하여 투여(7.0g 에탄올 및 39mg 하이드라진설페이트/kg 체중, 경구투여)한다. 에탄올을 부하한지 3시간, 24시간 및 72시간에서 동물의 사망 유무 및 생존예의 증상을 관찰하고 대조용(CMC 수용액 투여)과 비교한다. 대조용은 24시간까지에서 4마리/5마리, 72신까지에서 모두 사망한다. 한편, 본 조성물을 투여한 래트는 제3도에 도시한 바와 같이 저명하게 구명하여 72시간까지에서 알라닌 단독군 3/5; 글루타민 단독군 4/5; 알라닌과 글루타민의 몰비 1 : 0.2군 1/5; 1 : 1군 0/5; 1 : 5군 2/5였다(제3도 참조).10 week old Sprague-Dawley male rats weighing 300-340 g are given a feed containing 50% purified whole egg protein for 1 day. Stop feeding for 4 hours (from 9:00 am to 1:00 pm) in the bright period of the next day (7 am to 7 pm), then add 0.3% of L-alanine or L-glutamine alone or a combination of both Suspension in isopropyl solution (201 ml nitrogen / kg body weight, oral administration) in carboxymethyl cellulose (CMC) aqueous solution, and after 1 hour administration of 0.11% hydrazine sulfate in 20% ethanol-containing saline solution (7.0 g ethanol and 39 mg hydrazine) Sulfate / kg body weight orally). At 3, 24, and 72 hours of ethanol loading, the presence or absence of animal death and signs of survival were observed and compared with control (administration of aqueous CMC). The control dies in up to 4/5/72 gods up to 24 h. On the other hand, the rats to which the composition was administered were notably preserved as shown in FIG. Glutamine alone group 4/5; Molar ratio of alanine to glutamine 1: 0.2 / 5 group 1/5; 1:
[실시예 3]Example 3
체중이 300 내지 340g인 생후 10주의 스프라그-돌리 수컷 래트에게 50% 정제 전란 단백 함유 사료를 1일 동안 제공한다. 익일의 밝은 기간(오전 7시부터 오후 7시까지)에 4시간 동안 급식을 중단(오전 9시부터 오후 1시까지)한 다음, L-알라닌 또는 L-글루타민 단독 또는 양자의 배합 조성물을 0.3% 카복시메틸셀룰로오즈 수용액에 현탁시켜 등질소량 투여(201ml 질소/kg 체중, 경구투여)하고, 1시간 후에 20% 에탄올 함유 생리식염수에 0.13% 하이드라진 설페이트를 첨가하여 투여(6.0g 에탄올 및 39mg 하이드라진 설페이트/kg 체중, 경구투여)한다. 에탄올을 부하한지 3시간 및 24시간 후에 쇄골하 정맥으로부터 채혈하고, 대조용(CMC 수용액 투여)을 포함하여 혈중 간유래 효소 활성(GOT,GPT,OCT)의 변동을 조사군 사이에서 비교한다.10 week old Sprague-Dawley male rats weighing 300-340 g are given a feed containing 50% purified whole egg protein for 1 day. Stop feeding for 4 hours (from 9:00 am to 1:00 pm) in the bright period of the next day (7 am to 7 pm), then add 0.3% of L-alanine or L-glutamine alone or a combination of both Suspension in isopropyl solution (201 ml nitrogen / kg body weight, oral administration) in carboxymethylcellulose aqueous solution, and after 1 hour, 0.13% hydrazine sulfate was added to 20% ethanol-containing saline solution (6.0 g ethanol and 39 mg hydrazine sulfate / kg) Weight, oral administration). Blood is collected from the subclavian vein after 3 and 24 hours of ethanol loading, and changes in hepatic derived enzyme activity (GOT, GPT, OCT), including control (administration of CMC aqueous solution), are compared between the groups.
간에 특이적인 혈장 효소 활성인 GPT, OCT의 성적으로부터 알라닌 또는 글루타민 단독 투여에서도 급성 에탄올성 간 장해에 수반하는 양 활성 상승 억제 작용이 확인되었지만, 양자의 배함에 의해 이의 작용은 증강된다(제4도 참조).The results of GPT and OCT, which are the specific plasma enzyme activity in the liver, showed that alanine or glutamine administration alone inhibited both activity synergism with acute ethanolic liver disorders, but its action is enhanced by the excretion of both. Reference).
[실시예 4]Example 4
외래 진료를 받고 있는 대주가 간염 질환예 중에서 간염 바이러스 항체가 음성인 14명에게 L-알라닌과 L-글루타민으로 이루어진 조성물(알라닌과 글루타민의 몰비 1 : 0.12)을 1일당 3g(식후 30분에 1g씩 3회)씩 1 내지 6개월 동안 내복투여한다. 혈청 GPT, GOT, γ-GJP 각 효소 활성에 대하여 이상치를 나타낸 병례 중에서, GPT에서는 7예 중에서 6예, GOT에서는 9예 중에서 7예, γ-GTP에서는 14예 중에서 13예가 저하, 개선되었다(제5도 참조). 본 발명의 배합 조성물을 내복하는 도중에 부작용의 발현을 확인할 수 없는 탈락예도 없이 순조롭게 경과하여 관찰할 수 있으며 외래 환자의 경우에 단주는 곤란하므로 알콜성 간장해 개선 효과가 있다고 생각된다.Among the patients with outpatient hepatitis diseases, 14g of L-alanine and L-glutamine (molar ratio of alanine and glutamine 1: 0.12) were given to 14 patients with negative hepatitis virus antibody (1g at 30 minutes after meals). Three times each) for 1 to 6 months. Among the cases showing abnormal values for serum GPT, GOT, and γ-GJP enzyme activity, 13 out of 7 cases in GPT, 7 out of 9 cases in GOT, and 14 cases in γ-GTP were reduced and improved. See also 5). It can be observed that the progress of the compounding composition of the present invention can be observed smoothly without dropping out of the case that the expression of the side effects can not be confirmed, and in the case of an outpatient, the danju is difficult to improve alcoholic liver damage.
이상으로부터 명백한 바와 같이, 본 발명에 의하면, 실용성이 높은 우수한 간 장해 치료, 예방제를 제공할 수 있으므로 본 발명은 특히 의약품 산업에 있어서 극히 유용하다.As is apparent from the above, according to the present invention, the present invention is extremely useful especially in the pharmaceutical industry, because it is possible to provide a highly practical and effective liver disorder treatment and prevention agent.
제1도 혈장 에탄올의 농도; ⓐ 3시간, ⓑ 24시간.First concentration of plasma ethanol; Ⓐ 3 hours, ⓑ 24 hours.
제2도 에탄올 부하 20시간 경과후의 혼수상태로부터의 각성상태.Awakening from coma after 20 hours of ethanol loading.
평점 3 : 사망 또는 빈사 상태, 2 : 혼수, 1 : 의식 혼탁 및 행동억제, 0 : 각성.Rating 3: death or death status, 2: lethargy, 1: conscious turbidity and behavior suppression, 0: arousal.
제3도 에탄올 부하후의 생존율; ⓐ 투여 24시간 후, ⓑ 투여 72시간후.Third survival rate after ethanol loading; Ⓐ 24 hours after dosing, ⓑ 72 hours after dosing.
제4도 에탄올 부하후의 혈장 효소 활성.4. Plasma enzyme activity after ethanol loading.
제5도 대주가 간 장해 환자의 알라닌과 글루타민의 내복에 따른 간기능 검사치의 경과.The progress of the liver function test value according to the alanine and glutamine underwear of the patients with the main column 5 liver disorder.
Claims (8)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1019960017315A KR960016569B1 (en) | 1988-02-24 | 1996-05-22 | Food composition for alonine and glutamine |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP41368/1988 | 1988-02-24 | ||
| JP63-413368 | 1988-02-24 | ||
| JP63041368A JPH01216924A (en) | 1988-02-24 | 1988-02-24 | Therapeutic agent for hepatic disorder |
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| KR1019960017315A Division KR960016569B1 (en) | 1988-02-24 | 1996-05-22 | Food composition for alonine and glutamine |
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| KR890012644A KR890012644A (en) | 1989-09-18 |
| KR960008651B1 true KR960008651B1 (en) | 1996-06-28 |
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| KR1019880004617A KR960008651B1 (en) | 1988-02-24 | 1988-04-23 | Therapeutic preparation for the treatment of hepatic disorders |
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| US (1) | US4987123A (en) |
| EP (1) | EP0329879B2 (en) |
| JP (1) | JPH01216924A (en) |
| KR (1) | KR960008651B1 (en) |
| DE (1) | DE3883743T3 (en) |
| ES (1) | ES2059501T5 (en) |
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| US5189016A (en) * | 1990-05-18 | 1993-02-23 | Clintec Nutrition Co. | Nutrient compositions containing peptides and method for administering the same |
| CA2068333A1 (en) * | 1990-09-10 | 1992-03-11 | Austin L. Shug | Composition and method for protecting the heart during reperfusion |
| GB9121467D0 (en) * | 1991-10-10 | 1991-11-27 | Sandoz Nutrition Ltd | Improvements in or relating to organic compounds |
| JP3168669B2 (en) * | 1992-02-26 | 2001-05-21 | 味の素株式会社 | Liver regeneration promoter |
| AU6232794A (en) * | 1993-01-29 | 1994-08-15 | Brigham And Women's Hospital | The use of nitric oxide-delivering compounds for the treatment or prevention of alcoholic liver injury |
| DE69530570T2 (en) * | 1994-01-11 | 2004-03-18 | Stichting, Zofia | METHOD FOR TREATING HUMAN OR ANIMAL BODY DISTURBATION BY ADMINISTRATING AMINO ACIDS |
| US5561111A (en) * | 1994-12-23 | 1996-10-01 | The University Of Virginia Patent Foundation | Stable glutamine derivatives for oral and intravenous rehydration and nutrition therapy |
| WO2000068251A1 (en) | 1999-05-07 | 2000-11-16 | The University Of Virginia Patent Foundation | Biological production of stable glutamine, poly-glutamine derivatives in transgenic organisms and their use for therapeutic purposes |
| GB0114419D0 (en) * | 2001-06-13 | 2001-08-08 | Mars Uk Ltd | Health food |
| SE0201713D0 (en) | 2001-11-23 | 2002-06-06 | Gramineer Internat Ab | New methods and use III |
| JP4559380B2 (en) * | 2002-03-01 | 2010-10-06 | 日清ファルマ株式会社 | Liver disease treatment |
| TWI351278B (en) * | 2002-03-01 | 2011-11-01 | Nisshin Pharma Inc | Agent for preventing and treating of liver disease |
| US20060089412A1 (en) * | 2004-10-18 | 2006-04-27 | Ajinomoto Co. Inc. | Pharmaceutical composition for the treatment of non-alcoholic fatty liver disease |
| US20100016207A1 (en) * | 2005-11-10 | 2010-01-21 | Wurtman Richard J | Methods and Compositions for Raising Levels and Release of Gamma Aminobutyric Acid |
| JP5642922B2 (en) * | 2007-04-24 | 2014-12-17 | サントリーホールディングス株式会社 | Evaluation method of liver injury using multiple liver injury markers as indicators |
| JP2012041324A (en) * | 2010-08-23 | 2012-03-01 | Ajinomoto Co Inc | Inhibitor for deterioration of liver function, caused by administration of platinum-containing agent |
| CN103445175B (en) * | 2013-09-17 | 2014-10-08 | 深圳万和制药有限公司 | Composition with effects of alleviating hangover and protecting liver |
| JP2016086715A (en) * | 2014-10-31 | 2016-05-23 | アサヒグループホールディングス株式会社 | Food and drink containing component derived from carrot |
| CA2989743A1 (en) | 2015-06-19 | 2016-12-22 | Harsha CHIGURUPATI | Synergistic beverage composition |
| EP3257513A1 (en) | 2016-06-18 | 2017-12-20 | Chigurupati, Harsha | Composition to reduce dna and hepatic damage and to enhance repair thereof |
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| FR762M (en) * | 1960-08-31 | 1961-08-28 | ||
| FR2372626A1 (en) * | 1976-12-02 | 1978-06-30 | Sertog | THERAPEUTIC COMPOSITIONS BASED ON A PLANT EXTRACT AND AMINO ACIDS |
| JPS6150917A (en) * | 1984-08-20 | 1986-03-13 | Ajinomoto Co Inc | Remedying composition for alcoholic hepatopathy |
| US4870056A (en) * | 1986-01-23 | 1989-09-26 | Regents Of The University Of Minnesota | Acylated cyanamide composition |
| JPH0420409A (en) * | 1990-05-14 | 1992-01-24 | Daifuku Co Ltd | Conveyer apparatus capable of storing load |
-
1988
- 1988-02-24 JP JP63041368A patent/JPH01216924A/en active Pending
- 1988-02-26 DE DE3883743T patent/DE3883743T3/en not_active Expired - Lifetime
- 1988-02-26 ES ES88301678T patent/ES2059501T5/en not_active Expired - Lifetime
- 1988-02-26 EP EP88301678A patent/EP0329879B2/en not_active Expired - Lifetime
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| Publication number | Publication date |
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| DE3883743T3 (en) | 1997-12-04 |
| EP0329879B2 (en) | 1997-04-16 |
| DE3883743T2 (en) | 1994-03-17 |
| US4987123A (en) | 1991-01-22 |
| JPH01216924A (en) | 1989-08-30 |
| EP0329879A1 (en) | 1989-08-30 |
| KR890012644A (en) | 1989-09-18 |
| ES2059501T3 (en) | 1994-11-16 |
| EP0329879B1 (en) | 1993-09-01 |
| ES2059501T5 (en) | 1997-06-16 |
| DE3883743D1 (en) | 1993-10-07 |
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